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Adult T-cell leukemia/lymphoma (ATL) is an incurable peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I. In our preceding paper, 214 extracts from 162 plants were screened to elucidate the antiproliferative principles against ATL cell lines. Several withanolides were isolated and the structure-activity relationships (SAR) examined. To extend the search for SAR, 31 further withanolides, previously isolated from solanaceous plants, were tested against ATL cell lines. The presence of a 4β-hydroxy group as well as a 5β,6β-epoxy group appeared to be essential for the activity. In contrast, the presence of a sugar moiety at either the 3- or the 27-position led to a reduction in the activity. Furthermore, 24,25-dihydrowithanolide D (13) was identified as the most potent inhibitor, showing selective toxicity against ATL cell lines by inducing apoptotic cell death.

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1685 Poster Board I-711 Adult T-cell lymphoma/leukemia (ATLL) is a T-cell malignancy caused by human T-lymphotrophic virus type I (HTLV-I), and its therapeutic outcome is still remains very poor. Therefore, novel therapeutic strategies are needed to improve patient outcome. In this study, we elucidated the therapeutic potential to target anti-apoptotic Bcl-2 family proteins for the treatment of ATLL by using ABT-737 (Abbott Laboratories, Abbott Park, IL, USA), a small molecule inhibitor of Bcl-2, Bcl-XL and Bcl-w. We first validated the rationale of this study by assessing the expression of Bcl-2 family proteins among 25 lymph-node specimens derived from ATLL patients by using immunohistochemistory. Both or either of Bcl-2 and Bcl-XL proteins was highly expressed in 80% of specimens. We next examined the cytotoxicity of ABT-737 against ATLL cell lines. ABT-737 significantly inhibited growth of MT-1, MT-2 and HuT 102 cells with a concentration of 50 percent inhibition (IC50) at 72 h of 2.4, 0.23 and 0.008μM, respectively. We then elucidated the mechanism of growth inhibition induced by ABT-737 using MT-1 and MT-2 cells. ABT-737 induced apoptosis in MT-1, MT-2 cells with cleavage of caspase 9, 3 and PARP. ABT-737 also induced apoptosis in fresh tumor cells derived from patients with ATLL. We next elucidated the potential of ABT-737 to enhance the cytotoxicity induced by conventional chemotherapeutic agents. The interaction between them was evaluated using the Chou-Talalay method by determining the combination index. ABT-737 synergistically enhanced the cytotoxicity and apoptosis induced by either of doxorubicin, vincristine or etoposide, which is a current key drug to treat ATLL. Most importantly, ABT-737 significantly inhibited tumor growth of in vivo ATLL model using SCID mice inoculated by HuT 102 cells subcutaneously. The mean tumor volume, weight and serum level of soluble interleukin-2 receptor á of ABT-737 (100mg/kg/day)-treated mice were significantly lower than those of vehicle-treated mice after treatment for 21 days. Moreover, massive induction of apoptosis in tumors treated by ABT-737 was observed by immunofluorescent TUNEL assay. These results suggest that ABT-737 used either alone or in combination with conventional cytotoxic drugs, represents a promising novel targeted approach to overcome drug resistance and improve patient outcome in ATLL. Disclosures No relevant conflicts of interest to declare.

Combination therapy with interferon-α and zidovudine (IFN/AZT) has been regarded as standard care for acute and indolent (i.e., chronic and smouldering) ATL based on reports involving a limited number of patients. This treatment approach has not been evaluated in Japan, a major endemic area of this disease in the world. This is the first Japanese report of IFN/AZT for ATL. It is impossible to draw any definitive conclusion from this small study; however, IFN/AZT showed clear anti-ATL effects for refractory/relapsed ATL patients. This report would contribute for developing future ATL treatment in Japan.